Most chemical carcinogens induce DNA damage and are mutagenic at specific genetic loci; however, certain carcinogens (including the human carcinogens diethylstilbestrol, asbestos, arsenicals and benzene) usually do not induce gene mutations. We have examined the activity of these chemicals, proposed as carcinogenic but not mutagenic, to induce morphological transformation, gene mutations and chromosome mutations in Syrian hamster embryo cells in culture. Diethylstilbestrol (DES) induced cell transformation in the absence of mutations at specific genetic loci but was an inducer of aneuploidy by nondisjunction. DES was found to disrupt spindle microtubule organization in the cells and to cause chromosome loss and gain. Cell transformation and aneuploidy induction by DES were similar in terms of dose response and cell-cycle dependence. Furthermore, colcemid, a well known inducer of nondisjunction was also found to induce neoplastic transformation of cells in culture, confirming that aneuploidy induction is a potential mechanism for cell transformation. The mechanism of action of two other human carcinogens, asbestos and arsenic, were studied. Asbestos and other mineral fibers, including fiberglass, induced cell transformation in a dose dependent manner. The ability of fibers to induce cell transformation depended on fiber dimension, i.e., long, thin fibers were most potent. These findings indicate that this experimental system is a useful model to study the mechanism of fiber-induced tumorigenesis since similar results are found for fiber size dependence for mesothelioma induction in animals. An excellent correlation was observed between the induction of cell transformation and chromosome changes, including numerical and structural aberrations, suggesting that asbestos causes cell transformation by affecting chromosome stability. Arsenic also induced cell transformation and caused chromosome aberrations. The results with different carcinogens indicate that a significant effect of carcinogens is on chromosome number and structure and that these changes are important in the genesis of carcinogenesis.